Potentiation of beta-adrenergic inotropic response by pyruvate in failing human myocardium

Background: Pyruvate has been shown to increase contractile function in isolated myocardium and to improve hemodynamics in patients with congestive heart failure. We tested the hypothesis that pyruvate potentiates the inotropic response beta-adrenergic stimulation and to elevated extracellular calcium, since this may be of potential therapeutic value in the clinical setting of acute heart failure in order to circumvent deleterious effects on energy demand as can occur during catecholamine therapy. Methods and Results: We investigated isometrically contracting isolated multicellular muscle preparations from terminal failing human hearth at 37degreesC, pH 7.4, and a stimulation frequency of I Hz. At an extracellular calcium concentration of 1.25 mM, pyruvate ( 10 mM) alone increased developed force (F-dev) from 9.0+/-2.3 to 21.1+/-4.3 mN/mm(2) (n=9, P<0.001) and isoproterenol (1 muM) alone increased F-dev from 9.5+/-2.0 to 31.3+/-5.4 mN/mm(2) (P<0.001), whereas the combination of pyruvate and isoproterenol increased F-dev over-proportionally from 9.0+/-2.3 to 47.4+/-6.4 mN/mm(2) (P<0.01). In a separate series we assessed the combination of pyruvate and calcium. Although F-dev did not increase from 12 to 16 mM [Ca2+](o), 10 mM pyruvate further increased F-dev from 25.8+/-5.0 to 30.6+/-4.7 mN/mm(2) (P<0.01). Rapid cooling contractures revealed that altered myofilament responsiveness and/or sarcoplasmic reticulum (SR) calcium load must underlie the positive inotropic effect of pyruvate. Conclusion: A combination of pyruvate and P-adrenergic stimulation may be of therapeutic value in acute heart failure by reducing the concentrations of potential deleterious catecholamines that are currently necessary to maintain adequate tissue perfusion. (C) 2002 Elsevier Science BY All rights reserved.